Cathepsins B and D are considered to be two of the main catabolic proteinases. Cathepsins B and D have been suggested to play important roles in the metastatic potential of several types of cancer. Several investigators have found that metastatic B16 melanomas express highly elevated cathepsin B activity relative to non-metastatic melanomas. There is an increasing body of literature that links the cysteine protease cathepsin B with tumor malignancy. Also, a high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. In fact cathepsin B and D levels have recently been used as a markers to predict the prognosis of breast cancer and uterine cancer patients. A continuation of the design and the synthesis of (hydroxyethyl)amine isostere inhibitors of cathepsin D, which are similar to potent inhibitors of the aspartyl HIV-1 protease, are proposed. In the initial phase of this project some of these (hydroxyethyl)amine isosteres have proven to be very potent inhibitors of cathepsin D activity. In addition, the design and synthesis of aldehyde and thio-semicarbazone inhibitors of cathepsin B is also proposed. The new compounds will be evaluated for their inhibition of cathepsin B or D using appropriate proteinase assays. Detailed kinetic studies will then be performed and structure-activity correlations will be drawn for the synthetic inhibitors. This project is designed as a research effort, which will allow undergraduate students training in molecular modeling, organic synthesis, instrumental techniques, enzyme assays, kinetic studies, and statistical treatment of data through the enhancement of the research environment at this undergraduate institution.